Cardiovascular diseases are the principal cause of death in the United States today with 944,688 Americans dying in 1989 accounting for over 43% of all deaths. A reduction in blood pressure is associated with reduced morbidity and mortality of patients with high blood pressure. Calcitonin gene-related peptide is the most potent vasodilatory peptide occurring naturally. Structural features identified as important for its biological activity are the disulfide bridge between positions 2 and 7, the alpha- helix between positions 8 and 22, and the residue in position 14. human- alpha-CGRP (8-37) and [Tyr)O)-rat-alpha-CGRP (28-37) are competitive antagonists. The long term goal of this proposal is to gain insights into conformational and topographical properties of h-alpha-CGRP which are important for mediating its biological effects at its receptor. The general strategy is (i) to remove consecutive terminal amino acids not needed for biological activity, (ii) conformationally constrain regions of the peptide to favor putative bioactive conformations and (iii) obtain structure-activity profiles of positions identified as important for biological activity. Preliminary studies showed no amino acids can be removed from the C-terminus of h-alpha-CGRP without loosing biological activity. Local conformational constraints will be imposed on the C- terminal portion (residues 27-37) by substituting D-amino acids to stabilize putative beta-bends. Global constraints will be imposed on the flexibility of the disulfide bridge by substituting Pen residues for Cys residues. A structure-activity profile of residue 37, which we have previously shown to be essential for biological activity, will determine what functional groups the receptor will tolerate in this position. The importance of the C-terminal region of the antagonist, h-alpha-CGRP (8- 37), will be determined following strategies (i), (ii) and (iii) above. The relative importance of the C-terminal regions of the antagonist and the native peptide will be compared. A novel synthetic strategy involving the condensation of peptide fragments to a MBHA resin will be used to synthesize the peptide analogues. Fully protected fragments will be assembled on an oxime resin following Kaiser's protocols. Biological activity and binding affinity of the analogues will be assessed in pancreatic acinar cells, mesenteric artery and atria. Insights gained from this proposal will enable the design of potent selective agonists and antagonists of h-alpha-CGRP which will prove useful as pharmacological tools for the characterization of new CORP receptors. Furthermore, they will serve as excellent models for the design of therapeutically useful drugs to lower blood pressure.